We are studying the development and function of mucosal M cells and their role in immune surveillance. Our goal is to define the genes and mechanisms involved in the development and function of mucosal M cells. By identifying the critical steps and mechanisms in M cell biology, we will begin to establish their specific role in the mucosal immune response and its ability to mediate mucosal tolerance and the balance with commensal microbes. Our Working Hypothesis in these studies is that specific TNF Superfamily and TNF Receptor Superfamily genes along with coordinated expression of Jagged-1 mediate cellular interactions that specify M cell development and function. We will study two main steps in M cell development, defined by our studies on CD137- deficient mice. The first step is the commitment of M cell lineage progenitors from stem cells, which is dependent in part on ligands for the lymphotoxin receptors and the TNFa receptors. Expression of Jagged-1 by the established M cells may also inhibit generation of M cells from adjacent enterocytes. The second step, functional maturation of M cells, appears to be dependent on interactions between M cells and basolateral pocket B lymphocytes. Here, CD137 (TNFRSF9) and its ligand CD137L, may be an important signaling pair in this interaction. Two specific aims examine these components of our hypothesis: (1) How is M cell lineage commitment and development regulated by Jagged-1/Notch interactions? (2) What are the specific CD137/CD137L cellular interactions regulating M cell basolateral pocket formation and M cell functional development? Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies will provide important details on both the positive and negative regulators of this process.